Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells.
Immunity
; 54(6): 1137-1153.e8, 2021 06 08.
Article
em En
| MEDLINE
| ID: mdl-34051146
ABSTRACT
Alterations in the cGAS-STING DNA-sensing pathway affect intestinal homeostasis. We sought to delineate the functional role of STING in intestinal inflammation. Increased STING expression was a feature of intestinal inflammation in mice with colitis and in humans afflicted with inflammatory bowel disease. Mice bearing an allele rendering STING constitutively active exhibited spontaneous colitis and dysbiosis, as well as progressive chronic intestinal inflammation and fibrosis. Bone marrow chimera experiments revealed STING accumulation in intestinal macrophages and monocytes as the initial driver of inflammation. Depletion of Gram-negative bacteria prevented STING accumulation in these cells and alleviated intestinal inflammation. STING accumulation occurred at the protein rather than transcript level, suggesting post-translational stabilization. We found that STING was ubiquitinated in myeloid cells, and this K63-linked ubiquitination could be elicited by bacterial products, including cyclic di-GMP. Our findings suggest a positive feedback loop wherein dysbiosis foments the accumulation of STING in intestinal myeloid cells, driving intestinal inflammation.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Colite
/
Células Mieloides
/
Ubiquitinação
/
Disbiose
/
Imunidade Inata
/
Proteínas de Membrana
Tipo de estudo:
Observational_studies
/
Risk_factors_studies
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Immunity
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2021
Tipo de documento:
Article